The term "oral compositions" is used herein to designate products which in the ordinary course of usage are retained in the oral cavity for a time sufficient to contact substantially all of the dental and gingival surfaces, but which are not ingested. Such products include, for example, mouthwashes, sprays, dental gels, oral foams and dentifrices.
Dental plaque is a dense, tenacious deposit of oral bacteria. Calcification (mineralization) of dental plaque results in dental calculus. Calculus formation depends on the presence of plaque.
Plaque forms and grows on the surface of teeth, preferentially in the cervical, interdental and fissure areas and also on dental restorations, crowns, bridges and dentures. Plaque is the obligate cause of dental caries, and plaque and calculus are the causes of inflammatory destruction of the tooth-supporting gingival and periodontal structures (periodontitis).
A wide variety of chemical agents have been suggested to retard plaque formation and the resulting plaque diseases. Mechanical removal of plaque is attempted with oral hygiene measures, but average toothbrushing only partially results in plaque removal. Therefore, the additional use of chemical antibacterials inhibiting plaque formation in inaccessible dental areas is indicated. Germicides which have been proposed include phenolic compounds, halogenated bis-phenols (e.g. hexachlorophene), organic mercurials, hydroxyquinolines, iodine esters of hydroxybenzoic acids, chloramine T, and surface active compounds (detergents) among others. These germicides are excellent laboratory disinfectants but are relatively poor in vivo plaque inhibitors in contrast to cationic organic antibacterial agents, such as water soluble salts of cetylpyridinium, of quaternary ammonium bases (benzalkonium chloride), of alkylamines (fluoride of N,N,N'-tris-(2-hydroxyethyl)-N'-octadecyl-1,3-diaminopropane) and of cationic amidines, and water soluble salts of chlorhexidines, such as Hibitane, Alexidine and Vantocil.
The effect on plaque formation of mouthwashes used daily and containing cetylpyridinium chloride (Carter, H. G., Barnes, G. P.: Effects of three mouthwashes on existing dental plaque accumulations. J Prev Dent 2, 10, 1975; Ciancio, S. G., Mather, M. L., Bunnell, H. L.: Effect of a quaternary ammonium type mouthrinse on formed plaque. J Dent Res 54 A, Abstract 585, 1975), cetylpyridinium chloride plus a quaternary ammonium base (Domiphen bromide) (Barnes, G. P., Roberts, D. W., Katz, R. V., Woolridge, E. D.: Effects of two cetylpyridinium chloride-containing mouthwashes on bacterial plaque. J Periodontol 47, 419, 1976) or benzethonium chloride alone (Volpe, A. R., Kupczak, L. J., Brant, J. H., King, W. J., Kestenbaum, R. C., Schlissel, H. J.: Antimicrobial control of bacterial plaque and calculus and the effects of these agents on oral flora. J Dent Res 48, 832, 1969) is relatively modest when compared with amidines. This is evident when comparing mouthwashes containing chlorhexidine digluconate with other mouthwash antibacterials (Gjermo, P., Baastad, K. L., Rolla, G.: The plaque inhibiting capacity of 11 antibacterial compounds. J Peridont Res 5, 102, 1970; Muhlemann, H. R., Hulss, D., Steiner, E.: Antimicrobial rinses and proximal plaque on removable gold crowns. Helv Odont Acta 17, 89, 1973; and Bergenholtz, A., Hanstrom L.: The plaque-inhibiting effect of hexetidine (Oraldene.RTM.)-mouthwash compared to that of chlorhexidine. Community Dent Oral Epidemiol 2, 70, 1974.) Unfortunately, mouthrinsing with amidines will rapidly produce a cosmetically unacceptable brown stain on the teeth (Flotra, L., Gjermo, P., Rolla, G., Waerhaug, J.: Side effects of chlorhexidine mouthwashes. Scand J Dent Res 79, 119, 1971). Cationic detergents and amidines have also been found to irritate the oral mucosa even when used at recommended therapeutic concentrations in rinsing solutions (Flotra, L.: Different modes of chlorhexidine application and related local side effects. J Periodont Res 8, Supp. 12, 41, 1973).
The antiplaque properties of metal ions were mentioned as early as 1940 (Hanke, M. T.: Studies on the local factors in dental caries. I. Destruction of plaque and retardation of bacterial growth in the oral cavity. JADA 27, 379, 1940). U.S. Pat. No. 593,485 refers to zinc phenolsulfonate as bactericide. The use of zinc oxide or zinc phosphate for the stabilization of dental creams is described in U.S. Pat. No. 3,622,662. Zinc oxide and zinc sulphate are described in U.S. Pat. No. 3,624,199 for the same purpose. Effervescent antiplaque tablets containing zinc chloride are described in U.S. Pat. No. 3,888,976. Pader (U.S. Pat. No. 4,082,841) reported the anticalculus effect of zinc ions. A composition reducing the formation of dental calculus is reported in German Pat. No. 2,203,379.
Various zinc salts have been studied in clinical trials to determine their antiplaque potential when used in mouthwashes, but the results were conflicting. A zinc chloride solution at 1000 ppm zinc concentration was reported in one study to be effective (Skjorland, K., Gjermo, P., Rolla, G.: Effect of some polyvalent cations on plaque formation in vivo. Scand J Dent Res 86, 103, 1978), and in another trial to be totally ineffective (Compton, F. H., Beagrie, G. S.: Inhibitory effect of benzethonium and zinc chloride mouthrinses on human dental plaque and gingivitis. J Clin Periodontol 2, 33, 1975). Soluble zinc citrate displays a small plaque inhibitory action at zinc concentrations of 600 ppm (Addy, M., Richards, J., Williams, G.: Effects of a zinc citrate mouthwash on dental plaque and salivary bacteria. J Clin Periodontol 7, 309, 1980) and 1000 ppm (Waler, S. M., Rolla, G.: Plaque inhibiting effect of combinations of chlorhexidine and the metal ions zinc and tin. A preliminary report. Acta Odontol Scand 38, 201, 1980), respectively. Zinc chloride rinses (Zn=1000 ppm) clearly depresses calculus formation (Schmid, M. O., Schait, A., Muhlemann, H. R.: Effect of a zinc chloride mouthrinse on calculus deposits formed on foils. Helv Odont Acta 18, 22, 1974), and zinc chloride bound to carboxy-sulphate- and phosphate groups were reported to have deodorant properties. Zinc chloride complexed to polymers of carboxyl sulfate and phosphate groups prevents or controls mouth odor.
In recent years mechanisms of plaque inhibiting properties of metal ions have become increasingly evident (White, S. T., Taylor, P. P.: The effect of stannous fluoride on plaque scores. J Dent Res 58, 1850, 1979; Svatun, B., Gjermo, P., Eriksen, H. M., Rolla, G: A comparison of the plaque-inhibiting effect of stannous fluoride and chlorhexidine. Acta Odontol Scand 35, 247, 1977; Hock J., Tinanoff, N.: Resolution of gingivitis in dogs following topical applications of 0.4% stannous fluoride and toothbrushing. J Dent Res 58, 1652, 1979). Plaque apparently is only loosely adsorbed on the enamel in the presence of metal ions. Metal ions also interfere with the metabolic (enzymatic) activity of bacteria, particularly with acid formation from dietary carbohydrates. From among ions of silver, zinc, magnesium, tin and aluminum, stannous ions seem to possess the highest antiplaque activity (Svatun, B.: Plaque-inhibiting effect of dentifrices containing stannous fluoride. Acta Odontol Scand 36, 205, 1978; Gjermo, P., Rolla, G.: Plaque inhibition by antibacterial dentifrices. Scand J Dent Res 78, 464, 1970). Unfortunately, it is difficult to prevent hydrolysis and precipitate formation in mouthwashes containing water-soluble tin salts (Shannon, I. L. and Gibson, W. A.: Shelf life of aqueous solutions of stannous fluoride. USA School of Aerospace Medicine, Brooks Air Force Base, Texas, SAM-TDR-63-104). In addition, stannous fluoride is known to stain teeth. Yellowish discoloration is not known to occur with the use of zinc ions, such as zinc fluoride, zinc acetate and zinc chloride.
A mouthwash containing a 0.22% zinc chloride (Lavoris) has been marketed in the U.S. for many years. There is general agreement that zinc salts have a beneficial adstringent effect on inflamed oral mucosae and that they are modest plaque inhibitors.
Antiplaque and anticalculus effects have been claimed for zinc ions combined with tetradecylamine (U.S. Pat. No. 4,146,607), with glycine (British Patent Application GB No. 2,052,978 A), and with enzymes (U.S. Pat. No. 4,082,841). The combination of zinc salts with amidines (EPC Patent Application No. 0,026,252) is reported to prevent tooth discolorations without loss of amidine antiplaque action.
Antiplaque effects of oral rinses containing zinc salts and antibacterials have been reported in U.S. Pat. No. 4,022,880. The combination of zinc with antibacterials has been described in U.S. Pat. No. 4,022,880. Claims are only made for additive effects: "Our discovery concerns the co-action of zinc ions and an antibacterial agent, rather than a well defined synergistic property" ( column 4 of U.S. Pat. No. 4,022,880). The antibacterials listed in U.S. Pat. No. 4,022,880 are amidines, quaternary ammonium bases, phenolics a.s.o., but not pyrimidine amine bases nor hexetidine specifically. In addition many zinc salts are referred to, but not zinc fluoride. However, some scientific investigations have shown possible incompatibilities between solutions of zinc salts and quaternary ammonium bases. In another trial, zinc acetate combined with chlorhexidine digluconate was found to be slightly but not significantly superior in antiplaque action when compared with chlorhexidine alone (Waler, S. M., Rolla, G., supra).
Hexetidine, a saturated pyrimidine derivate, the analytical profile of which was recently reported, (Satzinger, G., Herrmann, W., Zimmermann, F.: Analytisches Profil des Rein-Hexetidins. Drug Research 25, 1849, 1975. (Godecke AG, Freiburg i.Br., West Germany)) has been used in mouthrinses for over 20 years. The chemical formula of Hexetidine is: ##STR1## 1,3-bis(2-ethylhexyl)hexahydro-5-methyl-5-pyrimidineamine.
Well known marketed mouthwashes containing 0.1 to 0.2 percent hexetidine are Drossadine, Hexoral, Hextril, Oraldene, Sterisol. They have been mainly recommended as pre- and postoperative astringent oral antiseptics and for the elimination of unpleasant breath.
Antiseptic oral effects of hexetidine, its depressive action on inflammed oral mucosae and its deodorant effects in the oral cavity were for the first time extensively reported in 1958 at a Symposium on Hexetidine, Northwestern University, Chicago, Ill. (Godecke Publication report on Hexoral.RTM.; Report of Warner-Chilcott on Hextril.RTM.).
The plaque inhibiting action of 0.1 percent hexetidine alone is similar to zinc salt solutions, is relatively moderate, and is more than 50 percent smaller than 0.2 percent chlorhexidine digluconate rinses (Muhlemann, H. R., Hulss, D., Steiner, E.: Antimicrobial rinses and proximal plaque on removable gold crowns. Helv Odont Act 17, 89, 1973; Muhlemann, H. R.: Auf dem Weg zum sauberen Zahn? SWISS DENT 2, No. 1-2, 7, 1981; Muhlemann, H. R., Saxer, U. P.: Plaque inhibition by rinsing solutions containing aminefluoride, hexetidine and zinc ions. Preprinted Abstract No. 17, ORCA-Congress 1981, Erfurt, DDR; Saxer, U. P., Muhlemann, H. R.: Plaque-inhibiting effect of zinc ions and fluoride, hexetidine and their combinations. Preprinted Abstract No. 18, ORCA-Congress 1981, Erfurt DDR). In addition, there are indications that retention of hexetidine in the oral cavity after rinsing, and subsequent antiglycolytic effects in plaque are less pronounced than in the case of chlorhexidine (Hefti, A., Widmer, B.: Reduktion des Keimpegels in der Mundhohle vor zahnarztlichen Behandlungen durch Mundwasser und Mundantiseptika. Schweiz Mschr Zahnheilk 90, 73, 1980) and amine chloride (Breitenmoser, Th.: The antiglycolytic action on dental plaque of amine chloride. Helv Odont Acta 19, 13, 1975), respectively.
Plaque and calculus reduction studies with combinations of zinc salts and a water-insoluble pyrimidine base hexitidine have hitherto not been described in theliterature.